We propose to identify genes for extreme obesity in African-Americans. This population has a high prevalence and degree of obesity, large average family sizes, differences in inheritance patterns from other groups, and genetic admixture with Whites. These factors combine to make this group an ideal focus for a genetic study. We will obtain extensive weight and medical histories and evaluate the obesity phenotype through measures of height, weight, skinfolds, circumferences, body composition, metabolic rate and blood chemistry. To our knowledge, the proposed sample of extensively evaluated African-American families will become a unique scientific resource. Specifically, we propose: l. to develop new family samples suitable for quantitative and molecular genetic studies of obesity in African-American families: 165 multiplex nuclear families with large sibships that are segregating an extreme obesity phenotype. We will extend 10 of these families to include three generations. Families will have at least two extremely obese siblings, one normal weight adult sibling, and one normal weight parent. Families selected in this manner are more likely to be segregating obesity genes than are those selected in other ways. With these family resources we will. 2. search for linkage of obesity phenotypes to genetic markers using two strategies: highly polymorphic short sequence repeats identified by the polymerase chain reaction and chromosome locations and genes associated with obesity in humans or animals. We will conduct linage analyses of families using both non-parametric and parametric analytic methods to deal with probable genetic heterogeneity and multi-gene effects on obesity, including analyses of affected sibling and affected family member pairs and lod score analysis of multiplex families with large sibships. 3. to conduct test for genetic heterogeneity. The identification of human obesity genes will improve accuracy of genetic risk estimates, enhance the efficiency of prevention programs, and permit the development of effective and specific therapies.